Open access Research BMJ Open: first published as 10.1136/bmjopen-2017-020759 on 14 December 2018. Downloaded from Clinical and genetic associations of renal function and diabetic kidney disease in the United Arab Emirates: a cross-sectional study Wael M Osman,1 Herbert F Jelinek,2,3 Guan K Tay,1,4,5,6 Ahsan H Khandoker,6 Kinda Khalaf,6 Wael Almahmeed,7,8 Mohamed H Hassan,9 Habiba S Alsafar1,6 To cite: Osman WM, Jelinek HF, ABSTRACT Strengths and limitations of this study Tay GK, et al. Clinical and Objectives Within the Emirati population, risk factors and genetic associations of genetic predisposition to diabetic kidney disease (DKD) ► This cross-sectional study to determine the clini- renal function and diabetic have not yet been investigated. The aim of this research kidney disease in the United cal, laboratory and genetic associations of diabetic was to determine potential clinical, laboratory and reported Arab Emirates: a cross- kidney disease (DKD) and renal function traits in a genetic loci as risk factors for DKD. sectional study. BMJ Open sample of patients with type 2 diabetes mellitus was Research design and methods Four hundred and ninety 2018;8:e020759. doi:10.1136/ the first of its kind in a population of Arab ancestry unrelated Emirati nationals with type 2 diabetes mellitus bmjopen-2017-020759 from the United Arab Emirates. (T2DM) were recruited with and without DKD, and clinical ► A limitation inherent to this study was that the anal- ► Prepublication history for and laboratory data were obtained. Following adjustments this paper is available online. yses carried out did not include treatment modalities for possible confounders, a logistic regression model was To view these files, please visit due to patients having multiple conditions and treat- developed to test the associations of 63 single nucleotide the journal online (http:// dx. doi. ments, which made the models largely unstable and polymorphisms (SNPs) in 43 genetic loci with DKD (145 org/ 10. 1136/ bmjopen- 2017- difficult to interpret. 020759). patients with DKD and 265 without DKD). Linear regression ► Current analyses of the DKD genetic association had models, adjusted for age and gender, were then used to a statistical power of ~57%, suggesting that a larger Received 26 November 2017 study the genetic associations of five renal function traits, population sample across the Middle East is required Revised 18 October 2018 including 83 SNPs with albumin-to-creatinine ratio, 92 to discover novel clinical and genetic predisposition Accepted 20 November 2018 SNPs with vitamin D (25-OH cholecalciferol), 288 SNPs to DKD in the region with better statistical power. with estimated glomerular filtration rate (eGFR), 363 SNPs http://bmjopen.bmj.com/ with serum creatinine and 73 SNPs with blood urea. Results Patients with DKD, as compared with those (DKD) as one of the most frequent compli- without the disease, were mostly men (52%vs38% for cations of both types of diabetes. Globally, the controls), older (67vs59 years) and had significant rates prevalence of chronic kidney disease (CKD) of hypertension and dyslipidaemia. Furthermore, patients among adults in the general population is with DKD had T2DM for a longer duration of time (16vs10 1 years), which in an additive manner was the single reported to be around 10%. However, 20% factor that significantly contributed to the development of adults with type 2 diabetes mellitus (T2DM) of DKD (p=0.02, OR=3.12, 95% CI 1.21 to 8.02). Among are expected to develop DKD based on esti- on September 27, 2021 by guest. Protected copyright. the replicated associations of the genetic loci with mated glomerular filtration rate (eGFR) different renal function traits, the most notable included measurements (<60 mL/min/1.73 m2), while SHROOM3 with levels of serum creatinine, eGFR and DKD the number reaches 30%–50% based on 1 (Padjusted=0.04, OR=1.46); CASR, GC and CYP2R1 with the urinary albumin excretion levels. This vitamin D levels; as well as WDR72 with serum creatinine considerable variation is due to variances in and eGFR levels. settings, geographical area and ethnicity.2 Conclusions Associations were found between several Overall, the risk of DKD in T2DM is approx- © Author(s) (or their genetic loci and risk markers for DKD, which may 3 influence kidney function traits and DKD in a population of imately 2% per year. In the Arab world, the employer(s)) 2018. Re-use prevalence of DKD is also highly variable permitted under CC BY-NC. No Arab ancestry. commercial re-use. See rights (10.8%–61.2%)%) depending on the study and permissions. Published by design, population, sample selection, race, BMJ. age, sex, as well as diagnostic criteria among For numbered affiliations see INTRODUCTIOn other factors.4 Meta-analysis has shown that end of article. This overall dramatic worldwide increase in DKD is the leading cause of end-stage renal Correspondence to the number of people with diabetes has had disease (ESRD) in the Gulf Cooperation 5 Dr Habiba S Alsafar; a major impact on the increasing incidence Council (GCC) with a prevalence of ~17%. habiba. alsafar@ ku. ac. ae and prevalence of diabetic kidney disease Patients with ESRD have a 20% annual Osman WM, et al. BMJ Open 2018;8:e020759. doi:10.1136/bmjopen-2017-020759 1 Open access BMJ Open: first published as 10.1136/bmjopen-2017-020759 on 14 December 2018. Downloaded from mortality rate, which is higher than the rate for many the loss of renal function in patients with T2DM, in addi- solid cancers.6 In addition to increasing the risk of cardio- tion to the established risk factors for DKD such as age, vascular morbidity and mortality7 8, DKD is reported to be sex, diabetes duration, HbA1c, blood pressure, baseline the single strongest predictor of mortality in patients with eGFR and albumin-to-creatinine ratio.26 However, issues diabetes,9 with a 5-year survival in the range of 30%.10 such as whether the levels of these markers are affected The current trend suggests that the prevalence of DKD by genetic variations, and whether the encoding genes will continue to increase worldwide, leading to increased contribute to DKD development and progress need morbidity and mortality and imposing significant socio- further investigation. economic burdens on global healthcare systems.11 A The United Arab Emirates (UAE) is among the coun- thorough literature search reveals that there remains a tries with the highest prevalence rates of T2DM, obesity wide knowledge gap related to the understanding of risk and cardiovascular disease.27 28 AlSafar and colleagues factors and pathophysiological mechanisms associated have recently reported that approximately 80% of patients with DKD, especially in the GCC and Middle East. Since with T2DM within UAE present with at least one compli- ESRD can only be treated with highly invasive and costly cation associated with T2DM, including kidney disease procedures, such as dialysis or kidney transplantation, (approximately 6%).29 Furthermore, there is increasing better knowledge of genetic, clinical and epidemiological evidence suggesting that the genome structure of individ- factors associated with DKD is required to allow for timely uals of Arabic descent is different from individuals from and more effective treatment options. other populations.30 Despite the high prevalence rate of In clinical practice, renal function is assessed using a DKD in the UAE, there have been no investigations up to number of tests that are reported to have high heritability date of the genetic associations of chronic kidney condi- rates.12 This indicates that genetic factors contribute tions and kidney functions, particularly as associated with significantly to interindividual variance in kidney func- T2DM. Therefore, the current work aimed to investigate tion, and hence, to the susceptibility to CKD and related the clinical and laboratory variables linked to DKD in a conditions. Thus far, several genetic loci have been linked T2DM Emirati population and to study the associations to DKD, CKD and renal function traits in adults13–24 as of the reported genetic loci linked to different renal func- well as children.25 However, in comparison with other tion tests in CKD and DKD. diseases, including T2DM and other cardiometabolic disorders, studies of kidney disease and kidney function traits are largely insufficient and inconclusive. In spite of MATERIALS AND METHODS efforts to describe novel biomarkers for DKD, currently no Study type and subjects tested candidates outperform albumin. A recent report This work describes a cross-sectional study of Emirati by Saulnier et al suggests that three serum biomarkers patients from the city of Abu Dhabi. The demographic (midregional-proadrenomedullin, soluble tumour information and clinical data for the participants are http://bmjopen.bmj.com/ necrosis factor receptor 1 and N-terminal prohormone presented in tables 1 and 2. Four hundred and ninety brain natriuretic peptide) can improve risk prediction of (n=490) patients with T2DM were included in the study, Table 1 Baseline data of tested traits and tested SNPs Mean±SD or N of subjects N of SNPs Trait quartiles (male/female) reported* N of SNPs tested* Covariates on September 27, 2021 by guest. Protected copyright. ACR (mg/mmol) 1.05/3.9/12.7† 115 (56/59) 331 83 Age and gender. Vitamin D (ng/mL) 63.7±27.8 328 (146/182) 442 92 Age and gender. eGFR (ml/ 81.5±28.5 395 (172/223) 1478 288 Age and gender. min/1.73 m2) Serum creatinine 60/74/95.8† 474 (246/228) 1792 363 Age and gender. (µmol/L) Blood urea 6.4±5.4 450 (263/214) 446 73 Age and gender. (mmol/L) Diabetic kidney With: 145. 288 63 Age, gender, disease Without: 265. hypertension, T2DM duration and eGFR levels.